A typical biological stress involved in the onset of diabetes is oxidative stress. Further, a new biological stress called endoplasmic reticulum stress has been found recently; research has gradually revealed that, similar to biological stress, endoplasmic reticulum stress is considered relevant to diabetes.
Endoplasmic reticulum stress designates an accumulation of irregular proteins in the endoplasmic reticulum. More specifically, endoplasmic reticulum stress is caused by failure of proper folding of proteins due to physical or chemical stimulation exerted on unstable incomplete proteins during the biosynthesis in the endoplasmic reticulum. In the endoplasmic reticulum, the unstable incomplete proteins during the biosynthesis are susceptible to physical or chemical stimulation, and such stimulation converts the proteins into abnormal proteins having an abnormal folding structure. Although the properly folded proteins are transported from the endoplasmic reticulum to the Golgi apparatus, the unfolded or misfolded proteins are stored inside the endoplasmic reticulum.
Cells are assumed to address endoplasmic reticulum stress using at least three methods below.
(1) a method of increasing the amount of molecular chaperones or the like in the endoplasmic reticulum, thereby protecting the proteins accumulated in the endoplasmic reticulum (UPR: unfolded protein response);
(2) a method of reducing the amount of protein entering into the endoplasmic reticulum, thereby reducing the load; and
(3) a method of degrading proteins accumulated in the endoplasmic reticulum by cytoplasm (ERAD: ER-associated protein degradation).
However, when the stress significantly outperforms these defense mechanisms, or when the defense mechanisms malfunction due to some sort of error, the stress is assumed to result in cell death. The characteristics of such cell death resulting from endoplasmic reticulum stress is morphologically the same as apoptosis, and is accompanied by expression induction or activation of molecules called CHOP, JNK, and caspase.
Recent study has revealed that such cell death derived from endoplasmic reticulum stress is deeply involved in various diseases including neurodegenerative disorders such as diabetes, Parkinson's disease, Alzheimer's disease, polyglutamine disease, prion disease, or amyotrophic lateral sclerosis (ALS); and ischemic disorders. Therefore, finding a method of overcoming cell death originating from endoplasmic reticulum stress is believed to provide a new treatment for various diseases.
Under such circumstances, research on the measurement of endoplasmic reticulum stress or the discovery of substances involved in endoplasmic reticulum stress has been conducted in various fields (for example, see Patent Documents 1 to 4). However, the relevance of certain substances to the mechanism of endoplasmic reticulum stress is still unclear.